Vascular disease can cause multi-infarct dementia. However in addition vascular disease and its associated risk factors such as hypercholesterolemia may also hasten the progression of Alzheimer's disease (AD). The long-range goal of this project is to determine the effect that systemic hypercholesterolemia and its associated vascular disease have on series of parameters of relevance to AD pathogenesis using hypercholesterolemic mice that are now widely used in atherosclerosis research. Specifically, we will utilize mice with a targeted disruption of the low-density lipoprotein receptor gene (LDLR -/- mice). By modulating the amount of cholesterol in the diet, plasma cholesterol in these mice can be widely varied and the degree of associated vascular disease reproducibly varied from minimal to severe. As biochemical markers of the AD process we will examine Abeta (Ab) production and tau phosphorylation. We will examine the functional consequences of hypercholesterolemia in these animals in two models of neural plasticity and repair, namely repair after entorhinal cortex lesioning and effect on neurogenesis in the adult hippocampus. A further functional correlate will be obtained through behavioral testing and since little is known about the effects of systemic hypercholesterolemia on brain cholesterol metabolism we will examine a series of parameters of cholesterol metabolism including 24S-hydroxycholesterol production in brain. To distinguish the effects hypercholesterolemia from its vascular consequences animals will be examined after short-term dietary manipulations when hypercholesterolemia is present but little vascular disease and after longer treatment intervals when significant vascular disease will be present. In each case both systemic and cerebral microvascular changes will be quantitatively assessed. Effects in LDLR -/- mice will be extended by determining if systemic hypercholesterolemia and vascular disease influence Ab production, plaque load and tau phosphorylation in the Tg2576 mouse model of AD by breeding the Tg2576 transgene onto an LDLR -/-background. Finally, we will examine Ab levels and tau conformational changes by ELISA in patient samples that have been scored for cerebrovascular pathology and amyloid pathology. Collectively these studies give us the opportunity to examine the effects of hypercholesterolemia and vascular disease on a series of AD related changes in both mouse and human material.